- Email: [email protected]
Deep-brain stimulation for dystonia: new twists in assessment
Reflection and Reaction
on the timing of the intervention. The pooled analysis did not show any difference between patients treated early (0–23 h) or late (24–48 h), but one of the three trials (HAMLET, which has a longer time window) is still ongoing and will probably provide more information. The pooled analysis takes us a big step forward in that it provides estimates of the effectiveness of decompressive surgery. Overall, it saves lives, albeit at the cost of more patients with moderate or moderately severe disability (but not severe disability). Centres that have already adopted this technique will undoubtedly feel encouraged to continue using it. Other centres will now have the evidence they need to take it up. Still, in order to guide the management of individual patients, we need more information about patients’ utility values for different outcomes after stroke and about the effects of treatment in different types of patients and in different time intervals after stroke onset. It is hoped that some of these questions will be addressed in later reports from the three trials or from future trials.
Eivind Berge Ullevaal University Hospital, Oslo, Norway [email protected] I have no conflicts of interest. 1 2
3
4
5
6
7 8
Frank JI. Large hemispheric infarction, deterioration, and intracranial pressure. Neurology 1995; 45: 1286–90. Hacke W, Berge E, Dennis M, Morley N. Decompressive surgery for malignant middle cerebral artery territory infarction. Practical Neurol 2002; 2: 144–53. Forsting M, Reith W, Schabitz WR, et al. Decompressive craniectomy for cerebral infarction: an experimental study in rats. Stroke 1995; 26: 259–64. Doerfler A, Forsting M, Reith W, et al. Decompressive craniectomy in a rat model of malignant cerebral hemispheric stroke: experimental support for an aggressive therapeutic approach. J Neurosurg 1996; 85: 853–59. Morley NCD, Berge E, Cruz-Flores S, Whittle IR. Surgical decompression for cerebral oedema in acute ischaemic stroke. Cochrane Database Syst Rev 2002; 3: CD003435. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6: 215–22. Post PN, Stiggelbout AM, Wakker PP. The utility of health states after stroke: a systematic review of the literature. Stroke 2001; 32: 1425–29. Holtkamp M, Buchheim K, Unterberg A, et al. Hemicraniectomy in elderly patients with space occupying media infarction: improved survival but poor functional outcome. J Neurol Neurosurg Psychiatry 2001; 70: 226–28.
Deep-brain stimulation for dystonia: new twists in assessment Primary generalised dystonia is a disabling neurological disorder that affects children and young adults for whom no effective medical treatment is available.1,2 Involuntary muscle spasms produce widespread abnormal movements and postures that can ultimately become devastating. Unlike secondary dystonia in Wilson’s disease and certain childhood metabolic brain disorders, primary dystonia is unaccompanied by other neurological findings. Genetic forms of primary generalised dystonia have been identified, but the cause is usually unknown.1,3 Neuropathological abnormalities have not been identified, but abnormal neuronal firing patterns4 and metabolic activity5 occur in the globus pallidus. Therapeutic benefit of pallidal deep-brain stimulation (DBS) is thought to be due to disruption of abnormal patterns of pallidal neuronal activity.4,6 DBS of the globus pallidus internus has been successfully used for treatment of dystonia but, until recently, evidence for efficacy has been limited to uncontrolled retrospective studies.2,6 Although controlled surgical trials are more difficult to undertake and can be controversial, these http://neurology.thelancet.com Vol 6 March 2007
trials with the use of blinded assessments are better than methods used to assess movement disorder surgery7 because placebo effects have occurred after fetal-tissue transplant surgery for Parkinson’s disease7 and medical treatment of dystonia.2,8 The long-term follow-up study by Vidailhet and co-workers published in this issue of The Lancet Neurology9 is a prospective but uncontrolled study reporting the 3 year follow-up results of a multicentre trial of bilateral pallidal DBS in 22 patients with primary generalised dystonia. In their previous publication10 about the same patient cohort followed up for 12 months after surgery, standardised video recordings were rated by a single investigator unaware of treatment allocation 3 months after surgery. The findings showed significant improvement in dystonia with stimulation on compared with stimulation off. Open assessment of dystonia and quality-of-life assessments showed that benefit was maintained at 12 months. Follow up was excellent in this multicentre trial. All 22 patients were reassessed 3 years after surgery, at which time 17 patients were receiving bilateral DBS
See Articles page 223
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Reflection and Reaction
and two were receiving unilateral DBS. The procedure was discontinued in several cases because of lead infection, lead fracture, stimulation-induced adverse effects, and lack of improvement. Treatment outcomes were generally similar to those of previous long-term retrospective studies.6 Improved motor, quality-of-life, cognitive, and depression scores at 12 months remained stable at 3 years. Stimulation settings did not change significantly over 3 years, indicating lack of tolerance to effects of long-term DBS. The important findings of this study are that motor and quality-of-life improvements were maintained for 3 years after surgery and were unaccompanied by altered cognitive function or mood. Identification of predictors of DBS responsiveness prior to submitting patients with dystonia to DBS would be useful. For example, previous studies have shown that primary generalised dystonia more commonly responds than do the secondary forms, which occur after brain injury.6 DYT1 gene status has not been a consistent predictive factor.6,8 In this study, DYT1 status, duration and severity of dystonia, age, and distribution of effective electrode contacts in the globus pallidus internus were not response predictors. However, patients with mobile or phasic movements improved more than those with relatively fixed tonic postures.10 This finding is in agreement with observations in other uncontrolled6 and controlled8 trials in which mobile dystonia improved soon after initiation of DBS whereas fixed postures were slower to respond. Although not a controlled trial, Vidailhet and colleagues’ initial 12 month study was a prospective trial with blinded assessments made by a single investigator with patients on and off stimulation.10 Because of concern for rebound dystonia after longer-term DBS,6,11 assessment off stimulation was not repeated in the 3 year study. In one type of controlled trial, patients could be randomly assigned electrode implantation or sham electrode implantation. However, DBS allows for a more acceptable and ethical trial design in which all patients undergo implantation followed by randomisation to either immediate or delayed DBS. This method has been used in delayed-start protocols of subthalamic DBS in Parkinson’s disease12 and of pallidal DBS in dystonia.8 In the delayed-start dystonia trial, electrodes were implanted in 40 patients with primary dystonia who were then randomly allocated either stimulation or sham stimulation for the first 3 months. 202
Patients were assessed by raters unaware of treatment allocation 3 months after surgery. Change in dystonia severity from baseline to 3 months was rated by blinded assessment of video recordings. Dystonia ratings improved by 39·3% in the stimulated group compared with 4·5% in the sham-stimulation group—results which are close to those reported at 3 months in Vidailhet and colleagues’ initial study.10 On the basis of this report and the controlled trial discussed above,8 pallidal DBS is safe and effective for primary dystonia. However, there remains a major need to identify predictive factors for responsiveness to DBS. Although secondary dystonia due to brain injury seems to respond poorly, there have been exceptions,6 whereas other secondary dystonias such as, for example, tardive dystonia and dystonia associated with pantothenate kinase-deficiency, have responded very well to pallidal DBS.1,13 Blinded ratings of dystonia and sham-controlled DBS should be encouraged as standard methodologies in future studies of DBS for dystonia as well as for other movement disorders in which DBS is to be assessed. Daniel Tarsy Parkinson’s Disease & Movement Disorders Center, Department of Neurology, Beth Israel Deaconess Medical Center, Boston MA 02215, USA [email protected] I have received unrestricted educational grants from Allergan Pharmaceuticals. 1 2 3 4
5 6 7 8 9
10
11 12 13
Tarsy D, Simon DK. Dystonia. N Engl J Med 2006; 355: 818–29. Bhidayasiri R, Tarsy D. Treatment of dystonia. Expert Rev Neurotherapeutics 2006; 6: 863–86. de Carvalho Aguiar PM, Ozelius LJ. Classification and genetics of dystonia. Lancet Neurol 2002; 1: 316–25. Vitek JL, Chockan V, Zhang JY, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999; 46: 22–35. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998; 44: 303–12. Krauss JK, Yianni J, Loher TJ, et al. Deep brain stimulation for dystonia. J Clin Neurophysiology 2004; 21: 18–30. Greene P. Deep-brain stimulation for generalized dystonia. N Engl J Med 2005; 352: 498–99. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006; 355: 20–32. Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral pallidal deep brain stimulation in primary generalized dystonia: a prospective three-year follow-up study. Lancet Neurol 2007; 6: 223–29. Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalzed dystonia. N Engl J Med 2005; 352: 459–67. Grabli D, Coelho-Braga M, Ewenczyk C, et al. Mov Disord 2006; 21 (suppl 15): S397–98. Deuschl G, Shade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355: 896–908. Castelnau P, Cif L, Valente EM, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol 2005; 57: 738–41.
http://neurology.thelancet.com Vol 6 March 2007
on the timing of the intervention. The pooled analysis did not show any difference between patients treated early (0–23 h) or late (24–48 h), but one of the three trials (HAMLET, which has a longer time window) is still ongoing and will probably provide more information. The pooled analysis takes us a big step forward in that it provides estimates of the effectiveness of decompressive surgery. Overall, it saves lives, albeit at the cost of more patients with moderate or moderately severe disability (but not severe disability). Centres that have already adopted this technique will undoubtedly feel encouraged to continue using it. Other centres will now have the evidence they need to take it up. Still, in order to guide the management of individual patients, we need more information about patients’ utility values for different outcomes after stroke and about the effects of treatment in different types of patients and in different time intervals after stroke onset. It is hoped that some of these questions will be addressed in later reports from the three trials or from future trials.
Eivind Berge Ullevaal University Hospital, Oslo, Norway [email protected] I have no conflicts of interest. 1 2
3
4
5
6
7 8
Frank JI. Large hemispheric infarction, deterioration, and intracranial pressure. Neurology 1995; 45: 1286–90. Hacke W, Berge E, Dennis M, Morley N. Decompressive surgery for malignant middle cerebral artery territory infarction. Practical Neurol 2002; 2: 144–53. Forsting M, Reith W, Schabitz WR, et al. Decompressive craniectomy for cerebral infarction: an experimental study in rats. Stroke 1995; 26: 259–64. Doerfler A, Forsting M, Reith W, et al. Decompressive craniectomy in a rat model of malignant cerebral hemispheric stroke: experimental support for an aggressive therapeutic approach. J Neurosurg 1996; 85: 853–59. Morley NCD, Berge E, Cruz-Flores S, Whittle IR. Surgical decompression for cerebral oedema in acute ischaemic stroke. Cochrane Database Syst Rev 2002; 3: CD003435. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6: 215–22. Post PN, Stiggelbout AM, Wakker PP. The utility of health states after stroke: a systematic review of the literature. Stroke 2001; 32: 1425–29. Holtkamp M, Buchheim K, Unterberg A, et al. Hemicraniectomy in elderly patients with space occupying media infarction: improved survival but poor functional outcome. J Neurol Neurosurg Psychiatry 2001; 70: 226–28.
Deep-brain stimulation for dystonia: new twists in assessment Primary generalised dystonia is a disabling neurological disorder that affects children and young adults for whom no effective medical treatment is available.1,2 Involuntary muscle spasms produce widespread abnormal movements and postures that can ultimately become devastating. Unlike secondary dystonia in Wilson’s disease and certain childhood metabolic brain disorders, primary dystonia is unaccompanied by other neurological findings. Genetic forms of primary generalised dystonia have been identified, but the cause is usually unknown.1,3 Neuropathological abnormalities have not been identified, but abnormal neuronal firing patterns4 and metabolic activity5 occur in the globus pallidus. Therapeutic benefit of pallidal deep-brain stimulation (DBS) is thought to be due to disruption of abnormal patterns of pallidal neuronal activity.4,6 DBS of the globus pallidus internus has been successfully used for treatment of dystonia but, until recently, evidence for efficacy has been limited to uncontrolled retrospective studies.2,6 Although controlled surgical trials are more difficult to undertake and can be controversial, these http://neurology.thelancet.com Vol 6 March 2007
trials with the use of blinded assessments are better than methods used to assess movement disorder surgery7 because placebo effects have occurred after fetal-tissue transplant surgery for Parkinson’s disease7 and medical treatment of dystonia.2,8 The long-term follow-up study by Vidailhet and co-workers published in this issue of The Lancet Neurology9 is a prospective but uncontrolled study reporting the 3 year follow-up results of a multicentre trial of bilateral pallidal DBS in 22 patients with primary generalised dystonia. In their previous publication10 about the same patient cohort followed up for 12 months after surgery, standardised video recordings were rated by a single investigator unaware of treatment allocation 3 months after surgery. The findings showed significant improvement in dystonia with stimulation on compared with stimulation off. Open assessment of dystonia and quality-of-life assessments showed that benefit was maintained at 12 months. Follow up was excellent in this multicentre trial. All 22 patients were reassessed 3 years after surgery, at which time 17 patients were receiving bilateral DBS
See Articles page 223
201
Reflection and Reaction
and two were receiving unilateral DBS. The procedure was discontinued in several cases because of lead infection, lead fracture, stimulation-induced adverse effects, and lack of improvement. Treatment outcomes were generally similar to those of previous long-term retrospective studies.6 Improved motor, quality-of-life, cognitive, and depression scores at 12 months remained stable at 3 years. Stimulation settings did not change significantly over 3 years, indicating lack of tolerance to effects of long-term DBS. The important findings of this study are that motor and quality-of-life improvements were maintained for 3 years after surgery and were unaccompanied by altered cognitive function or mood. Identification of predictors of DBS responsiveness prior to submitting patients with dystonia to DBS would be useful. For example, previous studies have shown that primary generalised dystonia more commonly responds than do the secondary forms, which occur after brain injury.6 DYT1 gene status has not been a consistent predictive factor.6,8 In this study, DYT1 status, duration and severity of dystonia, age, and distribution of effective electrode contacts in the globus pallidus internus were not response predictors. However, patients with mobile or phasic movements improved more than those with relatively fixed tonic postures.10 This finding is in agreement with observations in other uncontrolled6 and controlled8 trials in which mobile dystonia improved soon after initiation of DBS whereas fixed postures were slower to respond. Although not a controlled trial, Vidailhet and colleagues’ initial 12 month study was a prospective trial with blinded assessments made by a single investigator with patients on and off stimulation.10 Because of concern for rebound dystonia after longer-term DBS,6,11 assessment off stimulation was not repeated in the 3 year study. In one type of controlled trial, patients could be randomly assigned electrode implantation or sham electrode implantation. However, DBS allows for a more acceptable and ethical trial design in which all patients undergo implantation followed by randomisation to either immediate or delayed DBS. This method has been used in delayed-start protocols of subthalamic DBS in Parkinson’s disease12 and of pallidal DBS in dystonia.8 In the delayed-start dystonia trial, electrodes were implanted in 40 patients with primary dystonia who were then randomly allocated either stimulation or sham stimulation for the first 3 months. 202
Patients were assessed by raters unaware of treatment allocation 3 months after surgery. Change in dystonia severity from baseline to 3 months was rated by blinded assessment of video recordings. Dystonia ratings improved by 39·3% in the stimulated group compared with 4·5% in the sham-stimulation group—results which are close to those reported at 3 months in Vidailhet and colleagues’ initial study.10 On the basis of this report and the controlled trial discussed above,8 pallidal DBS is safe and effective for primary dystonia. However, there remains a major need to identify predictive factors for responsiveness to DBS. Although secondary dystonia due to brain injury seems to respond poorly, there have been exceptions,6 whereas other secondary dystonias such as, for example, tardive dystonia and dystonia associated with pantothenate kinase-deficiency, have responded very well to pallidal DBS.1,13 Blinded ratings of dystonia and sham-controlled DBS should be encouraged as standard methodologies in future studies of DBS for dystonia as well as for other movement disorders in which DBS is to be assessed. Daniel Tarsy Parkinson’s Disease & Movement Disorders Center, Department of Neurology, Beth Israel Deaconess Medical Center, Boston MA 02215, USA [email protected] I have received unrestricted educational grants from Allergan Pharmaceuticals. 1 2 3 4
5 6 7 8 9
10
11 12 13
Tarsy D, Simon DK. Dystonia. N Engl J Med 2006; 355: 818–29. Bhidayasiri R, Tarsy D. Treatment of dystonia. Expert Rev Neurotherapeutics 2006; 6: 863–86. de Carvalho Aguiar PM, Ozelius LJ. Classification and genetics of dystonia. Lancet Neurol 2002; 1: 316–25. Vitek JL, Chockan V, Zhang JY, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999; 46: 22–35. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998; 44: 303–12. Krauss JK, Yianni J, Loher TJ, et al. Deep brain stimulation for dystonia. J Clin Neurophysiology 2004; 21: 18–30. Greene P. Deep-brain stimulation for generalized dystonia. N Engl J Med 2005; 352: 498–99. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006; 355: 20–32. Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral pallidal deep brain stimulation in primary generalized dystonia: a prospective three-year follow-up study. Lancet Neurol 2007; 6: 223–29. Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalzed dystonia. N Engl J Med 2005; 352: 459–67. Grabli D, Coelho-Braga M, Ewenczyk C, et al. Mov Disord 2006; 21 (suppl 15): S397–98. Deuschl G, Shade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355: 896–908. Castelnau P, Cif L, Valente EM, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol 2005; 57: 738–41.
http://neurology.thelancet.com Vol 6 March 2007